Synthesis of Selenium-Decorated N-Oxide Isoquinolines: Arylseleninic Acids in Selenocyclization Reactions

Herein, we describe the use of benzeneseleninic acid derivatives (BSA) as a bench-stable and easy to handle selenium reagent to access 4-(selanyl)isoquinoline-N-oxides through the selenocyclization of o-alkynyl benzaldehyde oximes. The reaction is conducted in refluxing methanol, allowing the thermal generation of electrophilic selenium species in situ. By this new protocol, a library of 19 selenium-decorated N-oxide isoquinolines was accessed in up to 96% yield with an outstanding substrate tolerance and the feasibility to scale it up 10 times (from 0.25 to 2.5 mmol).


■ INTRODUCTION
N-Based heterocycles are a remarkable class of compounds widely found in nature, which play a pivotal role in the pharmaceutical industry due to their outstanding bioactivity, high stability, and operational efficiency in the human body. 1 The importance of these compounds can be summarized by considering that they are broadly found on the main structural core of important worldwide-marketed drugs, 2 including (1) Cephalexin, 3 an antibiotic used for the treatment of several bacterial infections, (2) Ramipril, 4 used for the treatment of hypertension, and (3) Acyclovir, 5 an antiviral medicine used for the treatment of some sexually transmitted virus, including herpes virus (Figure 1A).Isoquinoline-based alkaloids are particularly interesting compounds, which are present in several plants used in traditional Chinese medicine.For instance, Berberine demonstrated neuroprotective 6 and anticancer activities, 7 while Nuciferine has neuroprotective 6 and anti-inflammatory ones 8 (Figure 1B).In this context, N-oxide heterocycles (derived from pyridine, quinoline, and isoquinoline cores) are a privileged class of compounds with a large scope of applications in materials science. 9Additionally, they present relevant pharmacological activities, including antimicrobial, antiviral (HIV), antifungal, and anticancer ones. 10herefore, interest in the development of efficient synthetic protocols to access this class of compounds has been growing steadily in recent years, and several approaches have appeared in the literature. 11Considering isoquinoline N-oxide derivatives, the major strategies to prepare them are based on the electrophilic cyclization of o-alkynyl benzaldehyde oxime derivatives in the presence of transition metal (TM) catalysts or electrophilic species, which in general are generated in situ by oxidative events (Figure 1C). 12nother outstanding class of bioactive molecules is the organoselenium compounds, which have demonstrated important pharmacological activities.A notable example is Ebselen, which is widely known as a GPx-mimic antioxidant agent, 13 which very recently has demonstrated antiviral activity against SARS-CoV-2 virus. 14A significant part of the synthetic bioactive organoselenium derivatives are obtained when hybridized with N-based heterocycles, 15 as, for example, in the case of some selenium-decorated quinoline derivatives, which have demonstrated superior anti-inflammatory activity in comparison to Meloxicam. 16In this context, the main effective synthetic strategies to install organoselenium groups are through the use of Se-based electrophilic reagents (e.g., PhSeCl and PhSeBr) and by the generation in situ of related species in the presence of TM-based catalyst (e.g., Cu, Fe, and Ag) 17 or oxidant species (e.g., I 2 , Oxone, and persulfates). 18ithin this framework, some of us 19 have reported for the first time the synthesis of 4-(selanyl)isoquinoline-N-oxides 3 by reacting o-alkynyl benzaldehyde oximes 1 and diorganyl diselenides in the presence of Oxone under ultrasound irradiation.Although exhibiting short reaction times and an outstanding yield range, important drawbacks are still faced in this reaction, like the requirement for using high oxidant loading, increasing the generation of waste at the end of the process (Scheme 1A).
On the other hand, benzeneseleninic acid (BSA, 2) derivatives are inodorous and easy to handle reagents, besides being bench stable, not requiring special storage conditions.Recently, we have devoted our energy to demonstrate the synthetic applicability of BSA as a Se-based reagent to deliver Se(II)-decorated structures, under thermal and photocatalytic conditions, not requiring the use of strong oxidant species, reaction auxiliaries, or additives. 20Another important feature of BSA is that after the reaction water is the only produced waste.
Thus, as a continuation of our efforts to demonstrate the fabulous applicability of BSA as an electrophilic selenium precursor reagent, we depict herein an efficient protocol to prepare 4-(selanyl)isoquinoline-N-oxides 3 by reacting oalkynyl benzaldehyde oxime 1 and BSA 2 derivatives under thermal conditions, circumventing the use of strong oxidant conditions (Scheme 1B).
Based on our recent results on the thermal selenylation of heteroarenes, 20a,d we started our studies by stirring a mixture of substrates 1a (0.25 mmol) and 2a (0.5 mmol) in DMF at 80 °C for 16 h.Under these conditions, the desired isoquinoline N-oxide derivative 3a was obtained in only 27% yield (Table 1, entry 1).Then, the reaction temperature was increased to 120 °C; however, a huge decrease in reaction efficiency was observed, and the product 3a was isolated in 6% yield (Table 1, entry 2).Following, an extensive solvent screening study was performed at different temperatures, employing several protic and aprotic polar solvents, like t BuOH, i PrOH, EtOH, MeOH, glycerol, DCE, and MeCN (Table 1, entries 3−9).
In general, a very expressive improvement was achieved with MeOH presenting outstanding performance when used at reflux temperature, affording the product 3a in 96% yield (Table 1, entry 6).Following, the reaction time was reduced from 16 h to 8 and 4 h, allowing the obtention of 3a in 96% and 54% yields, respectively.Thus, 8 h was set as the best reaction time (Table 1, entries 10 and 11).Therefore, the reaction stoichiometry was tuned to 1:1, and the yield of 3a decreased to 79% yield (Table 1, entry 12).Finally, by conducting the process at room temperature, the formation of product 3a was completely suppressed and the starting materials were recovered (Table 1, entry 13).
With the best reaction conditions in hand (Table 1, entry 10), a broad reaction scope study was performed, employing several substrates 1a−f and 2a−g to construct a wide library of Scheme 1. Synthetic Approach for the Synthesis of Se-Decorated N-Oxide Isoquinolines a In a round bottomed flask, 2-alkynylbenzaldoxime 1a (0.25 mmol), benzeneseleninic acid 2a (0.5 mmol), and the solvent (1.0 mL) were added.The resulting mixture was heated using an oil bath (tabled temperatures), and the system was stirred by the indicated time.After workup, the reaction crude was purified by column chromatography.b A 0.25 mmol amount of 2a was used.ND = not detected.
The Journal of Organic Chemistry organoselenium-decorated N-oxide isoquinoline derivatives 3a−r (Table 2).Initially, benzeneseleninic acid 2a reacted with several 2-(phenylethynyl)benzaldehyde oximes 1b−d, bearing electron-rich and chloro-substituted aromatic rings attached to the C�C bond.All substrates have demonstrated outstanding suitability to the protocol, affording the corresponding products 3b, 3c, and 3d in 83%, 89%, and 85% yields, respectively.Following, the ability of other BSA derivatives 2 to be employed as substrate in the reaction was evaluated.Thus, p-methyl-and p-fluoro-substituted benzeneseleninic acids 2b and 2c were reacted with 1a to be converted to the respective N-oxide isoquinoline derivatives 3e and 3f, which were correspondingly isolated in 87% and 90% yields.Notably, the electron-deficient m-trifluoromethylbenzeneseleninic acid 2d reacted smoothly with 1a to afford the respective product 3g in 94% yield.Additionally, bulky BSA derivatives 2e and 2f (naphthyl and mesityl derivatives) were satisfactorily used to be converted to products 3h and 3i in 80% and 81% yields, respectively.These results highlight an important protocol feature, that is, the feasibility of application of sterically hindered substrates, without remarkable loss of efficiency.The chloro-containing o-alkynyl benzaldehyde oxime 1d satisfactorily reacted with p-methyl-and p-fluorosubstituted benzeneseleninic acids 2b and 2c to deliver the corresponding compounds 3j and 3k in 72% and 80% yields.These results also emphasize the protocol suitability for reactions among o-alkynyl benzaldehyde oxime 1a−d and BSA 2a−g derivatives, overcoming such electronic and steric effects (Table 2).
In the sequence, the C�C−TMS-derived o-alkynyl benzaldehyde oxime 1e was employed as substrate in the reaction with BSA 2a.Surprisingly, at the end of the process, the expected TMS-containing product 3l′ was not observed, and the C3-unsubstituted 4-(phenylselanyl)isoquinoline 2oxide 3l was exclusively obtained in 56% yield.Therefore, the terminal o-alkynyl benzaldehyde oxime 1f was reacted with electron-rich and -deficient BSA derivatives 2b, 2g, and 2d to be efficiently converted to the C3-unsubstituted products 3m, 3n, and 3o in 70%, 76%, and 94% yields, respectively.These results open synthetic possibilities, allowing the application of these products in further transformations in the C3 reaction site (Table 2).
Finally, the effect of the presence of an alkyl substituent at the C�C bond was evaluated by using the n Bu-attached oalkynyl benzaldehyde oxime 1g in reactions with BSA derivatives 2a, 2b, and 2g under the optimal conditions.Satisfactorily, C3-alkyl products 3p, 3q, and 3r were afforded in 72%, 52%, and 79% yields, also demonstrating the versatility of the protocol in efficiently delivering 3-alkyl-substituted products (Table 2).Additionally, benzylic seleninic acid 2h reacted smoothly with o-alkynyl benzaldehyde oxime 1a to afford the corresponding product 3s in 61% yield.This result indicates that the C(sp 3 )−Se bond remains intact in the reaction.
Aiming to investigate the protocol usefulness, a scale-up experiment was performed, increasing the reaction scale by 10 times (from 0.25 to 2.5 mmol).Accordingly, the reaction of 1a with 2a was satisfactorily conducted, remarkably affording the expected product 3a in 85% yield (0.801 g).Furthermore, the In a round-bottomed flask, a mixture of substrate 1 (0.25 mmol) and 2 (0.5 mmol) in MeOH (1.0 mL) was stirred for 8 h under reflux using an oil bath.All products (3a−s) were purified by column chromatography.

The Journal of Organic Chemistry
Se-decorated N-oxide isoquinoline 3a was employed as substrate in some synthetic transformations.First, 3a was reacted with MsCl in water to give 3-phenyl-4-(phenylselanyl)isoquinolin-1(2H)-one 4 in 63% yield. 21Moreover, 3a also reacted with o-bromo ynone 5 in the presence of K 2 CO 3 , under thermal conditions, to be smoothly converted to the polycyclic product 6 by the simultaneous C−N and C−C bond construction (Scheme 2). 22 view of the excellent outcomes on the use of BSA 2 as a selenylating agent in the selenocyclization of o-alkynyl benzaldehyde oximes 1, several control experiments were conducted to gain influential mechanistic insights.Initially, the standard reaction condition (Table 1, entry 10) was performed in the presence of diphenyl diselenide (DPDS, 7) as substrate instead of BSA 2a, and the formation of product 3a was not observed, demonstrating that even if PhSeSePh is formed by thermal decomposition of 2a, it is not reactive enough to trigger the transformation.We also observed that in the absence of BSA, the corresponding product from the intramolecular cyclization of 1a (compound 8) was not formed, pointing out that the main reaction pathway does not follow a previous intramolecular annulation of 1a (Scheme 3).
Following, a one-pot experiment was run by generating BSA 2a in situ (PhSeSePh + H 2 O 2 ) and subsequent addition of 1a (1 equiv).Under this condition, the desired product 3a was achieved poorly in 42% yield (vs 74% yield starting from BSA; see Table 1, entry 12).Even though this result shows that a one-pot strategy is not advantageous, in view of the facility to afford BSA 2a purely, it also highlights the mandatory presence of BSA 2a as reagent for the success of the transformation.Aiming to verify if the main reaction pathway involves radical events, two experiments were carried out in the presence of 3 equiv of radical scavengers (TEMPO and hydroquinone).In both, no significant change in the reaction efficiency was observed, suggesting that the main reaction events follow ionic pathways (Scheme 3).
Based on these results and on our previous advances in the chemistry of BSA, 20 a plausible reaction mechanism was proposed.Initially, the process is fully dependent on a thermal decomposition of BSA 2a toward PhSeSePh 7.This hypothesis was experimentally confirmed by submitting just 2a under the optimized reaction conditions.The development of a yellowish color was observed, and subsequently, the presence of a small amount of 7 was confirmed by 77 Se NMR.Besides, it is supported by the fact that the transformation is completely suppressed when the reaction is conducted at room temperature (Table 1, entry 13), pointing out a pivotal thermal decomposition of 2a.Following, under heating, 2a and 7 can undergo a comproportionation process to the selenium electrophilic species I and II. 23Finally, these species are eventually protonated to reach the intermediates III, which are more electrophilic to react with the C�C bond present in 1a, delivering the seleniranium intermediate IV.To verify the reasonableness of these events (the comproportionation in the presence of DPDS 7 and the protonation of intermediates I and II), 1a was reacted with a mixture of 2a and DPDS 7 (2:1 ratio) in the presence of 1 equiv of p-toluenesulfonic acid (TsOH), yielding the product 3a in 92% yield.Finally, the intramolecular annulation of IV drives the transformation toward the cyclized intermediate V, which is finally Scheme 2. Scale-up Experiments and Synthetic Applications of 3a

Scheme 3. Control Experiments and Plausible Mechanism
The Journal of Organic Chemistry deprotonated to be converted to the desired product 3a (Scheme 3, plausible reaction mechanism).

■ CONCLUSIONS
An alternative protocol to prepare Se-decorated isoquinoline N-oxide derivatives in moderate to excellent yields (52−96%) was developed by reacting o-alkynyl benzaldehyde oximes and benzeneseleninic acid derivatives under thermal conditions.The strategy allowed conducting reactions in the absence of oxidant and other auxiliary species, delivering mild, safe, and easy to handle procedures.Besides, the protocol presents outstanding substrate suitability, demonstrating tolerance to electron-donating and -withdrawing groups attached to aromatic systems as well as to alkyl groups linked to the C�C bond.Taken together, these features point out a new avenue of applications of BSA derivatives as a source of Se(II) electrophilic species under thermal conditions, performing electrophilic cyclization processes under oxidant-and metalfree mild reaction conditions.
■ EXPERIMENTAL SECTION General Information.The reactions were monitored by TLC carried out on Merck silica gel (60 F 254 ).For visualization, TLC plates were either placed under UV light, stained with iodine vapor and 5% vanillin in 10% H 2 SO 4 and heat.Column chromatography was performed using Merck Silica Gel (pore size 60 Å, 230−400 mesh).Low-resolution mass spectra (MS) were measured on a Shimadzu GC-MS-QP2010 mass spectrometer.The HRMS analyses were performed in a HESI Quadrupole-Orbitrap (Q extractive focus, Thermo Scientific) spectrometer equipped with an APCI source operating in positive mode.The samples were solubilized in methanol and analyzed by direct infusion at a constant flow rate.The acquisition parameters were: Scan type Full MS; resolution 70000; polarity positive.Ionization conditions HESI: Sheath gas 20; aux gas 10; spray voltage 2.8 kV; capillary temperature 300 °C.The mass-tocharge ratio (m/z) data were processed and analyzed using Bruker Daltonics softwares: Compass Data Analysis and Isotope Pattern.Hydrogen nuclear magnetic resonance ( 1 H NMR), Carbon-13 nuclear magnetic resonance ( 13 C{ 1 H} NMR), and Selenium-77 nuclear magnetic resonance ( 77 Se{ 1 H} NMR) were obtained on Bruker Avance III HD spectrometer at 400, 100, 76, and 400 MHz, respectively.Spectra were recorded in CDCl 3 solutions.Chemical shifts (δ) are reported in ppm, referenced to tetramethyl silane (TMS, δ 0.0 ppm) as the internal reference for 1 H NMR and the solvent peak of CDCl 3 (δ 77.23 ppm) for 13 C{ 1 H} NMR.Coupling constants (J) are reported in hertz.The 77 Se{ 1 H} NMR chemical shifts are reported in ppm relative to the external reference (C 6 H 5 Se) 2 (δ 463 ppm).Abbreviations to denote the multiplicity of a particular signal are s (singlet), d (doublet), dd (doublet of doublets), ddd (doublet of doublet of doublets, td (triplet of doublets), tt (triplet of triplets), q (quartet), and m (multiplet).Melting point (mp) values were measured in a Marte PFD III instrument.The o-alkynyl benzaldehyde oximes 1a−g were prepared by already described protocols. 24The and arylseleninic acids 2a−g were previously prepared as described in the Supporting Information. 25eneral Procedure for the Synthesis of 3-Organyl-4-(selanyl)isoquinoline-2-oxides (3a−3s).To a 10.0 mL glass tube were added the appropriate oxime 1 (0.250 mmol, 1 equiv), arylseleninic acid 2 (0.5 mmol, 2 equiv), and MeOH (1.0 mL, 0.25 M).The resulting solution was stirred under reflux for 8 h.Posteriorly, the solvent was evaporated, and the crude product was purified via column chromatography using a 10:90 MeOH:EtOAc mixture as the eluent, affording the corresponding product 3.

Table 1 .
Reaction Optimization Study for the Synthesis of 3a a